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bioRxiv · 10.1101/265884

Immune evasion and immunotherapy resistance via TGF-beta activation of extracellular matrix genes in cancer associated fibroblasts

Chakravarthy, A.·Khan, L.·Bensler, N. P.·Bose, P.·De Carvalho, D. D.
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Abstract

The ability to disseminate, invade and successfully colonise other tissues is a critical hallmark of cancer that involves remodelling of the extracellular matrix (ECM) laid down by fibroblasts 1. Moreover, Cancer-Associated-Fibroblasts (CAFs) produce key growth factors and cytokines as components of the ECM that fuel tumour growth, metastasis and chemoresistance, and immune response 2-4. ECM changes also predict prognosis in pancreatic 5 and colorectal cancers 6,7. Here, we examine the landscape of ECM-gene dysregulation pan-cancer and find that a subset of ECM genes is (i) dysregulated specifically in cancer, (ii) adversely prognostic, (iii) linked to TGF-beta signalling and transcription in Cancer-Associated-Fibroblasts, (iv) enriched in immunologically active cancers, and (v) predicts responses to Immune checkpoint blockade better than mutation burden, cytolytic activity, or an interferon signature, thus identifying a novel mechanism of immune evasion for patient stratification in precision immunotherapy and pharmacological modulation.

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Chakravarthy, A., Khan, L., Bensler, N. P., Bose, P., De Carvalho, D. D.. 2018-02-15. Immune evasion and immunotherapy resistance via TGF-beta activation of extracellular matrix genes in cancer associated fibroblasts. https://doi.org/10.1101/265884

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